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About
This is a Phase 0/1 open-label, non-randomized, biomarker and pharmacodynamic study in patients with advanced B-cell lymphoid malignancies, including B-cell chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), acute lymphocytic leukemia (ALL), multiple myeloma (MM), Waldenström's macroglobulinemia (WM), mantle cell lymphoma, follicular lymphoma, or diffuse large B-cell lymphoma (DLBCL) who have failed at least one prior therapy and for whom no standard curative therapy exists. Patients with advanced stage disease are those whose disease is resistant or refractory to standard chemotherapy or biological therapies.
Full description
This pilot study will evaluate whether the administration of roflumilast inhibits the activity of PDE4 and results in the modulation of AKT/mTOR pathways in patients with B-cell hematologic malignancies. Peripheral blood samples will be collected for the purpose of determining the pharmacodynamics of roflumilast on PDE4 activity and on biomarkers as related to GC resistance. Samples are obtained at baseline prior to starting study treatment, on Day 8 before the administration of the Day 8 study drugs (prednisone and roflumilast), and on Day 15. If a bone marrow biopsy is also performed prior to study treatment or at any time during treatment, a sample will be sent for analysis. Normal PBMC (and bone marrow when it is obtained) will be examined for changes in key targets related to the inhibition of PDE4 and potential reversal of glucocorticoid resistance. Biomarker blood samples will be analyzed in order to characterize the pharmacodynamics of roflumilast alone and in combination with prednisone on PDE4 activity and on biomarkers, such as phospho-AKT, phosphorylation levels of mTOR targets.
Enrollment
Sex
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Volunteers
Inclusion criteria
Signed informed consent.
Men and women > 18 years of age
Diagnosed with relapsed or refractory (per investigator assessment) B-cell hematologic malignancy, including CLL, SLL, ALL, MM, WM, mantle cell lymphoma, follicular lymphoma, or DLBCL that has progressed or recurred following prior therapy. Patients must have failed, refused, be ineligible, or not otherwise appropriate for any potential standard curative treatment. In addition, patients must be refractory to or intolerant of established therapy known to provide clinical benefit for their condition. The original diagnostic biopsy and/or other diagnostic data (e.g., cell marker data) will suffice.
Has failed ≥ 1 previous treatment for their malignancy, and has relapsed or refractory disease following most recent prior treatment.
ECOG performance status of ≤ 2 and a life expectancy of at least 3 months.
Ability to swallow oral tablets without difficulty.
All subjects with preserved reproductive potential must agree to practice abstinence or employ contraceptive measures for the duration of treatment and for 4 weeks following final dosing.
Has recovered from adverse, toxic effects of prior therapies to ≤ Grade 1(NCI-CTCAE v4) except for alopecia and peripheral neuropathy. This requirement will be subordinate to specific clinical and laboratory criteria that are otherwise specifically addressed in these inclusion/exclusion criteria. Peripheral neuropathy must have recovered to ≤ Grade 2 except for patients with WM, who may enroll with Grade 3 peripheral neuropathy if due to the underlying WM.
Meet the following clinical laboratory requirements:
All patients, except ALL:
For patients with ALL and CLL:
The hematological criteria do not apply.
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
10 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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